Current studies concentrate on comprehensive tests of hypothalamic-pituitary function and on the measurement and administration of endogenous neuropeptides or their analogs. Major findings this year are: the plasma half-life of corticotropin releasing factor (CRF) in humans is greater than for any other known endogenous hypothalamic hormone. Administration of 1ug/kg of CRF at 20:00 h constitutes a clinically applicable test of the human hypothalamic-pituitary-adrenal (HPA) axis. For instance, in contrast to normal volunteers, drug-free bipolar subjects, regardless of clinical state, show a significant growth hormone response to CRF. In addition, drug-free bipolar depressed patients show blunted ACTH responses, to CRF, indicating normal feedback regulation of cortisol on ACTH secretion at the pituitary, and suggesting increased hypothalamic CRF secretion as the basis for hypercortisolism in depression. To support this hypothesis, continuous CRF infusion to normals produced hypercortisolism of the magnitude typically seen in depression. Patients with Cushing's disease, in contrast to depressed patients, show a robust response to ACTH despite high baseline cortisol values, reflecting a marked impairment of feedback regulation at the pituitary. Thus, the responses to CRF suggest that the pathophysiologic locus of HPA regulation is different in depression and Cushing's disease and the CRF stimulation test may aid in the differential diagnosis of the two entities.